US8299022B2ActiveUtilityPatentIndex 84
Analogs of ghrelin substituted at the N-terminal
Est. expirySep 27, 2026(~0.2 yrs left)· nominal 20-yr term from priority
Inventors:DONG ZHENG XIN
A61P 5/12A61P 43/00A61P 9/10A61P 5/00A61P 5/06A61P 5/10A61P 3/10A61P 5/02A61P 25/28A61P 3/00A61P 3/04A61P 3/02A61P 19/00A61P 19/10A61K 38/00A61P 21/00C07K 14/60A61P 1/08A61P 11/08A61P 1/10A61P 1/14A61P 1/06A61P 15/00A61P 11/06A61P 1/12A61P 11/00A61K 38/22C07K 14/575C07K 2/00
84
PatentIndex Score
11
Cited by
9
References
27
Claims
Abstract
The invention comprises peptidyl analogs of ghrelin having greater stability which are active at the GHS receptor according to formulae depicted below: (R 2 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -R 1 wherein the definitions of A 1 to A 28 , R 1 and R 2 are provided for in the specification, with the exception that the N-terminal amino acid must be selected from the group consisting of Inp, 1-Apc and 4-Apc, the pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising an effective amount of said compound together with therapeutic and non-therapeutic uses thereof.
Claims
exact text as granted — not AI-modified1. A ghrelin analog compound according to formula (I):
(R 2 )-A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -R 1 (I)
wherein:
A 1 is Inp, 1-Apc or 4-Apc;
A 2 is Ser, Abu, Acc, Act, Aib, Ala, Ava, Thr or Val;
A 3 is Ser, Asp(NH—R 3 ), Asp(O—R 4 ), Cys(S—R 5 ), Dab(S(O) 2 —R 6 ), Dap(S(O) 2 —R 7 ), Glu(NH—R 8 ), Glu(O—R 9 ), Ser(C(O)—R 10 ), Thr(C(O)—R 11 ) or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 4 is Phe, Acc, Aic, Cha, 2-Fua, 1-Nal, 2-Nal, 2-Pal, 3-Pal, 4-Pal, hPhe, (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, Taz, 2-Thi, 3-Thi, Trp or Tyr;
A 5 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle or Val;
A 6 is Ser, Abu, Acc, Act, Aib, Ala, Gly, Thr or Val;
A 7 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz or Tic;
A 8 is Glu, Acc, Aib, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 9 is His, Acc, Apc, Aib, 2-Fua, 2-Pal, 3-Pal, 4-Pal, (X 1 ,X 2 ,X 3 ,X 4 ,X 5 -)Phe, Taz, 2-Thi or 3-Thi;
A 10 is Gln, Acc, Aib, Asn, Asp or Glu;
A 11 is Arg, Apc, hArg, Dab, Dap, Lys, Orn or HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O);
A 12 is Val, Abu, Acc, Aib, Ala, Cha, Gly, Ile, Leu, Nle, Nva or Tle;
A 13 is Gln, Acc, Aib, Asn, Asp or Glu;
A 14 is Gln, Acc, Aib, Asn, Asp or Glu;
A 15 is Arg, Acc, Aib, Apc, hArg, Dab, Dap, Lys or Orn;
A 16 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn or deleted;
A 17 is Glu, Arg, Asn, Asp, Dab, Dap, Gln, Lys, Orn, Asp(NH—R 3 ), Asp(O—R 4 ), Cys(S—R 5 ), Dab(S(O) 2 —R 6 ), Dap(S(O) 2 —R 7 ), Glu(NH—R 8 ), Glu(O—R 9 ), Ser(C(O)—R 10 ), Thr(C(O)—R 11 ), HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O) or deleted;
A 18 is Ser, Abu, Acc, Act, Aib, Ala, Thr, Val or deleted;
A 19 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn or deleted;
A 20 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn or deleted;
A 21 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
A 22 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
A 23 is Ala, Abu, Acc, Act, Aib, Apc, Gly, Nva, Val or deleted;
A 24 is Lys, Acc, Aib, Apc, Arg, hArg, Dab, Dap, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O) or deleted;
A 25 is Leu, Abu, Acc, Aib, Ala, Cha, Ile, hLeu, Nle, Nva, Phe, Tle, Val or deleted;
A 26 is Gln, Aib, Asn, Asp, Glu or deleted;
A 27 is Pro, Dhp, Dmt, 3-Hyp, 4-Hyp, Inc, Ktp, Oic, Pip, Thz, Tic or deleted;
A 28 is Arg, Acc, Aib, Apc, hArg, Dab, Dap, Lys, Orn, HN—CH((CH 2 ) n —N(R 12 R 13 ))—C(O) or deleted;
R 1 is —OH, —NH 2 , —(C 1 -C 30 )alkoxy or NH—X 6 —CH 2 —Z 0 , wherein X 6 is a (C 1 -C 12 )alkyl or (C 2 -C 12 )alkenyl and Z 0 is —H, —OH, —CO 2 H or —C(O)—NH 2 ;
R 2 is, H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroallcyl, (C 1 -C 30 )acyl, (C 2 -C 30 )alkenyl, (C 2 -C 30 )alkynyl, aryl(C 1 -C 30 )alkyl, aryl(C 1 -C 30 )acyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 2 -C 30 )acyl, substituted (C 2 -C 30 )alkenyl, substituted aryl(C 1 -C 30 )alkyl, substituted (C 2 -C 30 )alkynyl or substituted aryl(C 1 -C 30 )acyl;
each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is, independently for each occurrence thereof, selected from the group consisting of (C 1 -C 40 )alkyl, (C 2 -C 40 )alkenyl, substituted (C 1 -C 40 ) alkyl, substituted (C 2 -C 40 ) alkenyl, alkylaryl, substituted alkylaryl, aryl and substituted aryl;
each of R 12 and R 13 is, independently for each occurrence thereof, selected from the group consisting of H, (C 1 -C 40 )alkyl, (C 1 -C 40 )heteroalkyl, (C 1 -C 40 )acyl, (C 2 -C 40 )alkenyl, (C 2 -C 40 )alkynyl, aryl(C 1 -C 40 )alkyl, aryl(C 1 -C 40 )acyl, substituted (C 1 -C 40 )alkyl, substituted (C 1 -C 40 )heteroallcyl, substituted (C 1 -C 40 )acyl, substituted (C 2 -C 40 )alkenyl, substituted (C 2 -C 40 )alkynyl, substituted aryl(C 1 -C 40 )alkyl, substituted aryl(C 1 -C 40 )acyl, (C 1 -C 40 )alkylsulfonyl or —C(NH)—NH 2 ;
n is, independently for each occurrence thereof, 1, 2, 3, 4 or 5;
each of X 1 , X 2 , X 3 , X 4 , and X 5 is, independently for each occurrence thereof, selected from the group consisting of H, F, Cl, Br, I, (C 1-10 )alkyl, substituted (C 1-10 )alkyl, aryl, substituted aryl, OH, NH 2 , NO 2 and CN;
provided that:
when R 12 is (C 1 -C 40 )acyl, aryl(C 1 -C 40 )acyl, substituted (C 1 -C 40 )acyl, substituted aryl(C 1 -C 40 )acyl, (C 1 -C 40 )alkylsulfonyl, or —C(NH)—NH 2 , then R 13 is H or (C 1 -C 40 )alkyl, (C 1 -C 40 )heteroalkyl, (C 2 -C 40 )alkenyl, (C 2 -C 40 )alkynyl, aryl(C 1 -C 40 )alkyl, substituted (C 1 -C 40 )alkyl, substituted (C 1 -C 40 )heteroalkyl, substituted (C 2 -C 40 )alkenyl, substituted (C 2 -C 40 )alkynyl, or substituted aryl(C 1 -C 40 )alkyl;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein:
A 2 is Ser or Aib;
A 3 is Ser or Glu(NH—R 8 );
A 4 is Phe;
A 5 is Leu;
A 6 is Ser;
A 7 is Pro;
A 8 is Glu or Aib;
A 9 is His;
A 10 is Gln or Aib;
A 11 is Arg;
A 12 is Val;
A 13 is Gln;
A 14 is Gln;
A 15 is Arg;
A 16 is Lys;
A 17 is Glu or Ser(C(O)—R 10 );
A 18 is Ser;
A 19 is Lys;
A 20 is Lys;
A 21 is Pro;
A 22 is Pro;
A 23 is Ala;
A 24 is Lys;
A 25 is Leu;
A 26 is Gln;
A 27 is Pro; and
A 28 is Arg;
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 2 , wherein:
R 1 is NH 2 ;
R 2 is H or acyl;
R 8 is hexyl; and
R 10 is octanyl;
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 3 , wherein:
A 2 is Aib;
A 3 is Glu(NH-hexyl);
A 8 is Aib;
A 10 is Aib; and
A 17 is Ser(n-octanoyl);
or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 4 , wherein said compound is selected from the group consisting of:
(SEQ ID NO: 5)
(Inp 1 )hGhrelin(1-28)-NH 2 ;
(SEQ ID NO: 6)
(Inp 1 , Aib 2 )hGhrelin(1-28)-NH 2 ;
(SEQ ID NO: 7)
(Inp 1 , Aib 2 , Glu(NH-hexyl) 3 )hGhrelin(1-28)-NH 2 ;
(SEQ ID NO: 8)
(Inp 1 , Aib 2, 10 )hGhrelin(1-28)-NH 2 ;
(SEQ ID NO: 9)
(Inp 1 , Aib 2, 8 )hGhrelin(1-28)-NH 2 ;
(SEQ ID NO: 10)
(Inp 1 , Aib 2 , Ser(n-octanoyl) 17 )hGhrelin(1-28)-NH 2 ;
(SEQ ID NO: 11)
(Inp 1 , Ser(n-octanoyl) 17 )hGhrelin(1-28)-NH 2 ;
and
(SEQ ID NO: 12)
(Inp 1 , Aib 2, 8 , Ser(n-octanoyl) 17 )hGhrelin(1-28)-
NH 2 ;
or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
(SEQ ID NO: 13)
[Inp 1 , Ser 3 ]hGhrelin(1-28)-NH 2 ;
(SEQ ID NO: 14)
[Inp 1 , Aib 2 , Ser 3 ]hGhrelin(1-28)-NH 2 ;
(SEQ ID NO: 15)
[Inp 1 , Aib 2 , Ser 3 , Ser(n-octanoyl) 17 ]hGhrelin
(1-28)-NH 2 ;
and
(SEQ ID NO: 16)
[Inp 1 , Aib 2 , 10 , Ser 3 ]hGhrelin(1-28)-NH 2 ;
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising an effective amount of a compound of according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
8. A method for stimulating growth hormone secretion in a subject in need of such stimulation, comprising the step of administering to said subject a therapeutically effective amount of a ghrelin analog compound or pharmaceutically acceptable salt thereof according to claim 1 wherein said effective amount is at least an amount sufficient to produce a detectable increase in growth hormone secretion.
9. A method according to claim 8 wherein said stimulation of growth hormone secretion is indicated for treating a growth hormone deficient state, for increasing muscle mass, for increasing bone density, for treating sexual dysfunction in males or females, for facilitating a weight gain, for facilitating maintenance of weight, for facilitating maintenance of physical functioning, for facilitating recovery of physical function, or for facilitating appetite increase.
10. A method according to claim 9 wherein said facilitating weight gain, facilitating maintenance in weight, or facilitating appetite increase is indicated in a patient having a disease or disorder or undergoing a treatment accompanied by weight loss.
11. A method according to claim 10 , wherein said weight loss is due to cachexia.
12. A method of treating chronic obstructive pulmonary disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a ghrelin analog compound or pharmaceutically acceptable salt thereof according to claim 1 .
13. A method of stimulating gastrointestinal motility in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a ghrelin analog compound or pharmaceutically acceptable salt thereof according to claim 1 .
14. A method according to claim 13 , wherein said patient in need of gastrointestinal stimulation is suffering from gastroesophageal reflux disease, ileus, post-operative ileus, emesis, gastroparesis, inflammatory bowel syndrome (IBS), constipation, or colonic pseudo-obstruction.
15. A method according to claim 14 , wherein said patient is suffering from ileus associated with the administration of an opiate.
16. A method according to claim 15 , wherein said postoperative ileus follows abdominal surgery.
17. A method according to claim 16 , wherein said ileus is of the stomach, small intestine, or large intestine.
18. A method according to claim 14 , wherein said patient is suffering from emesis associated with treatment with an anti-cancer chemotherapeutic agent, pregnancy, bulimia, or anorexia.
19. A method according to claim 14 , wherein said gastroparesis is associated with diabetes.
20. A method according to claim 13 , wherein said therapeutically effective amount of said ghrelin analog compound or composition is administered intravenously, subcutaneously, orally, or by implantation of a sustained release formulation.
21. A method of treating post-operative ileus in a patient in need thereof, wherein said method comprises administering to said patient a therapeutically effective amount of a ghrelin analog compound or pharmaceutically acceptable salt thereof according to claim 1 , before, during or after a surgery, or any combination thereof.
22. A method of treating gastroesophageal reflux disease, emesis, gastroparesis, irritable bowel syndrome (IBS), constipation, or colonic pseudo-obstruction in a patient in need thereof, wherein said method comprises administering to said patient a therapeutically effective amount of a ghrelin analog compound or pharmaceutically acceptable salt thereof according to claim 1 .
23. A method of treating post-operative ileus, gastroesophageal reflux disease, emesis, gastroparesis, irritable bowel syndrome (IBS), constipation, or colonic pseudo-obstruction in a patient in need thereof by administering to said patient a therapeutically effective amount of a ghrelin analog compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein said administration is intravenous, subcutaneous, oral, or by implantation of a sustained release formulation.
24. A compound according to claim 1 , wherein said compound is selected from the group consisting of:
(SEQ ID NO: 19)
(Ac-Inp 1 , Aib 2, 10 , Glu(NH-hexyl) 3 )hGhrelin(1-28)-
NH 2 ;
(SEQ ID NO: 20)
(Ac-1-Apc 1 , Aib 2, 10 , Glu(NH-hexyl) 3 )-hGhrelin
(1-28)NH 2 ;
(SEQ ID NO: 17)
(Inp 1 , Aib 2, 10 , Glu(NH-hexyl) 3 )hGhrelin(1-28)-NH 2 ;
and
(SEQ ID NO: 18)
(1-Apc 1 , Aib 2, 10 , Glu(NH-hexyl) 3 )-hGhrelin(1-28)
NH 2 ;
or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising an effective amount of a compound according to claim 24 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
26. A method for suppressing growth hormone secretion in a subject in need of such suppression, comprising the step of administering to a subject an effective amount of a ghrelin analog compound according to claim 24 , or a pharmaceutically acceptable salt thereof, wherein said effective amount is at least an amount sufficient to produce a detectable decrease in growth hormone secretion.
27. A method according to claim 26 , wherein said suppression of growth hormone secretion is indicated for the treatment of a disease or condition characterized by excessive growth hormone secretion, for facilitation of loss of excessive body weight, for facilitation of appetite decrease, for facilitation of weight maintenance, for treating obesity, for treating diabetes, or for treating complications with diabetes including retinopathy.Cited by (0)
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